Low-dose "metronomic chemotherapy" with oral cyclophosphamide and methotrexate in metastatic breast cancer: a case report of extraordinarily prolonged clinical benefit.

We report the case of a 34-year-old woman affected by breast cancer that had metastasized to the bone. She had been treated with oral cyclophosphamide and methotrexate (metronomic chemotherapy) and achieved 3.5 years of clinical remission. To our knowledge, this is the first description of such a prolonged response to therapy. This case report adds weight to known data on metronomic treatment and supports further investigation of this therapy.

Prospective phase II trial of cetuximab plus VMAT-SIB in locally advanced head and neck squamous cell carcinoma. Feasibility and tolerability in elderly and chemotherapy-ineligible patients.

INTRODUCTION: Cetuximab plus radiotherapy (RT) may be an effective alternative to chemoradiation in locally advanced head and neck squamous cell carcinoma (LASCCHN) patients. We analyzed a group of patients treated at our institute with cetuximab plus volumetric modulation arc therapy (VMAT) with the RapidArc technique in a simultaneous integrated boost (SIB) regime. The primary end point was the assessment of acute toxicity and the feasibility of the combined approach. MATERIALS AND METHODS: Between December 2008 and March 2010, 22 patients were submitted to IMRT-SIB plus cetuximab for radical intent in case of LASCCHN. None of the patients was suitable for chemotherapy because of important comorbidities (the majority suffered of heart chronic diseases). All patients underwent planning CT (additional image modalities were acquired for contouring purposes in the same treatment position: MRI in 12 and FDG-PET in 4 out of 22 patients). VMAT, by means of RapidArc, and SIB with two dose levels of 54.45 Gy and 69.96 Gy in 33 fractions were adopted. All patients included in the analysis were concomitantly treated with cetuximab: administration of the drug was initiated 1 week before RT at a loading dose of 400 mg/m(2) body surface area over a period of 120 min, follow by a weekly 60 min infusion of 250 mg/m(2) for the duration of RT. Patients were assessed for toxicities according to the Radiation Therapy Oncology Group (RTOG) criteria. RESULTS: All but 2 patients completed treatment and achieved the minimum follow-up of 12 months after the end of the treatment. Of the 22 patients, 18% (4 patients) showed grade 1, 36% (8 patients) grade 2, and 36% (8 patients) showed grade 3 dermatitis, while 9% (2 patients) had grade 1, 36% (8 patients) grade 2, and 45% (10 patients) had grade 3 mucositis/stomatitis. No grade 4 toxicities were recorded. Considering blood parameters, 3 cases of grade 1 anemia and 1 case of grade 2 thrombocytopenia were observed. Nobody required feeding tube placement during treatment. CONCLUSION: The here reported toxicity data are promising and encouraging in regard to the adoption of moderate hypofractionation with VMAT-SIB techniques, when cetuximab is concomitantly administered.

Outcome of T1N0M0 breast cancer in relation to St. Gallen risk assignment criteria for adjuvant therapy.

T1N0M0 (stage I) breast cancer (BC) has been increasing in recent decades but the optimal adjuvant approach remains controversial. To assess the outcome of BC patients stratified and treated with multimodal therapies according to St. Gallen consensus meeting recommendations, we retrospectively evaluated an unselected cohort of T1N0M0 BC patients, with respect to the St. Gallen criteria. At a median follow-up of 5 years, the recurrence rate, recurrence-free survival and overall survival were 7%, 94% and 96% respectively, and 60% of relapses were locoregional. No statistically significant difference was observed between T1a,b/T1c groups, or among risk categories (high/intermediate/low). The very low rate of distant recurrences even in patients with unfavorable prognostic factors seems to support the use of adjuvant systemic therapies but better prognostic and predictive factors are strongly needed for this subset of patients.

Role of cMET expression in non-small-cell lung cancer patients treated with EGFR tyrosine kinase inhibitors.

BACKGROUND: Approximately 10% of unselected non-small-cell lung cancer (NSCLC) patients responded to the epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) treatment. However, resistance mechanisms are not well understood. We evaluated several potential biological markers of intrinsic EGFR-TKIs-resistance in NSCLC. MATERIALS AND METHODS: pAKT, pERK, cSRC, E-cadherin, cMET[pY1003], cMET[pY1230/1234/1235], and cMET[pY1349] immunohistochemistry, cMET FISH analysis, and EGFR-, KRAS-, and cMET mutation analysis were carried out on tumor samples from 51 gefitinib-treated NSCLC patients. Biological parameters and survival end points were compared by univariate and multivariate analyses. cMET expression was also investigated in two additional series of patients. The in vitro antiproliferative activity of gefitinib alone or in combination with hepatocyte growth factor and the cMET antibody DN-30 was assessed in NSCLC cells. RESULTS: EGFR19 deletion and pAKT expression were significantly associated with response (P < 0.0001) and longer time to progression (TTP) (P = 0.007), respectively. Strong cMET[pY1003] membrane immunoreactivity was expressed in 6% of 149 tumors analyzed and was significantly associated with progressive disease (P = 0.019) and shorter TTP (P = 0.041). In vitro, the DN-30 combination synergistically (CI < 1) enhanced gefitinib-induced growth inhibition in all cMET[pY1003]-expressing cell lines studied. CONCLUSIONS: Activated cMET[pY1003] appears to be a marker of primary gefitinib resistance in NSCLC patients. cMET may be a target in treatment of NSCLC.

Primary chemotherapy followed by anterior craniofacial resection and radiotherapy for paranasal cancer.

BACKGROUND: To study prospectively the activity of primary chemotherapy with cisplatin, fluorouracil and leucovorin (PFL) in patients with paranasal cancer receiving surgery and postoperative radiotherapy. PATIENTS AND METHODS: Forty-nine patients, previously untreated, with resectable paranasal carcinoma were enrolled. PFL (leucovorin 250 mg/m2/day for 5 days as a 120 h continuous infusion (c.i.), 5-fluorouracil 800 mg/m2/day from day 2 as a 96 h c.i. and cisplatin 100 mg/m2 day 2 q 3 weeks) was planned for five courses. RESULTS: Thirty-two patients (65%) completed three or more chemotherapy courses. Two deaths from thrombotic events were observed after the first cycle. Eight cardiac toxicities were recorded during chemotherapy causing treatment discontinuation. Objective response to PFL was observed in 21 patients [43%; 95% confidence interval (CI) 29% to 58%], including four complete responses (CRs) (8%; 95% CI 2% to 20%) and 17 partial responses (PRs) (35%). Pathological complete remission (pCR) was achieved in eight of 49 patients (16%). At 3 years, overall survival was 69% and event-free survival 57%. Overall and event-free survival in patients achieving pCR is 100%. CONCLUSIONS: PFL is active in paranasal cancer. Patients who attain a pathological complete remission have a favorable prognosis. Cardiovascular complications represent the limiting toxicity. Primary chemotherapy combined with surgery-sparing treatment approaches deserves further investigation.

Irinotecan and raltitrexed: an active combination in advanced colorectal cancer.

BACKGROUND: Irinotecan and raltitrexed are active agents in metastatic colorectal cancer. Preclinical findings suggest a remarkable synergistic activity between the two drugs and the feasibility of this association has been shown in a recent phase I study. The aim of our phase II trial was to assess the efficacy and tolerability of the combination of irinotecan and raltitrexed in patients with metastatic colorectal cancer untreated with chemotherapy. PATIENTS AND METHODS: From June 1998 to February 2000, 46 patients were enrolled. Patients received irinotecan 350 mg/m(2) on day 1 and raltitrexed 2.6 mg/m(2) on day 2, every 3 weeks, for up to nine courses. Tumour assessment was performed every three cycles. RESULTS: A total of 223 cycles of chemotherapy, with a median number of six (range 1-9) courses per patient, was administered. According to intention-to-treat analysis, the overall response rate was 46% (95% confidence interval 31% to 61%). The median duration of response was 21 weeks (range 11-> or =101), the median time to progression 27 weeks (range 1-> or =116), and the median overall survival 57 weeks (range 1-> or =130). The main toxicities were diarrhoea, with National Cancer Institute common toxicity criteria grade 3/4 in 26% of patients, grade 3/4 neutropenia in 20%, grade 3 nausea-vomiting in 13%, grade 3 asthenia in 11% and grade 3/4 transaminase elevation in 4%. CONCLUSIONS: Results achieved with irinotecan and raltitrexed show that this regimen is active, despite 'not-negligible' toxicity, and may represent a useful regimen for specific subgroups of colorectal cancer patients.

Concurrent radiotherapy and weekly paclitaxel for locally advanced or recurrent squamous cell carcinoma of the uterine cervix. A pilot study with intensification of dose.

OBJECTIVE: This study included patients with inoperable primary or recurrent cervical cancer whose treatment plan called for exclusive radiotherapy. The endopoints of the study were to confirm the feasibility of concurrent radiotherapy and paclitaxel in relation to potential acute toxicity and to evaluate if an increase of complete local control might be obtained with the association of paclitaxel to radiotherapy as a radiosensitizer. METHODS: Twenty patients (13 new cases, stage IIB-III, and 7 with pelvic recurrences) were enrolled and, with exclusion of one recurrence, 19 were evaluable for acute toxicity and response. In new cases, radiotherapy was conventionally administered: 50.4 Gy/28 fractions by external beam (whole pelvis) followed by intracavitary cesium or reduced transcutaneous field. In recurrences, radiotherapy was performed with external beam only through individualized fields. Paclitaxel was administered weekly at the dose of 40 mg/m2 or 60 mg/m2 during the entire course of external radiotherapy. RESULTS: Complete regression (CR) as defined by clinical and imaging examinations was achieved in eight of the 13 new cases (62%) and in four of the six recurrences (66%), for a total complete response rate equal to 63%. Five patients (3 treated with 40 mg/m2 and 2 with 60 mg/m2) experienced grade 3 small bowel toxicity, one patient treated with 40 mg/m2 grade 3 bladder toxicity and one patient treated with 60 mg/m2 had grade 4 mucositis. Out of 12 CR patients at the end of treatment, ten maintain complete local remission for a median follow-up of 47 months but two have developed distant metastases. CONCLUSION: The results confirm that this approach is feasible and suggest the use of paclitaxel as radiosensitizer in locally advanced cervical cancer.

Clinical significance of neuroendocrine phenotype in non-small-cell lung cancer.

Non-small-cell lung carcinoma (NSCLC) describes a histologically heterogeneous group of tumours with variable clinical behaviour. Performance status, tumour stage and histological type have important prognostic implications, but clinical outcomes in individual patients remain unpredictable. A significant minority of NSCLCs (10%-30%) show neuroendocrine (NE) differentiation, and a number of studies have attempted to evaluate the therapeutic and prognostic significance of the expression of NE markers on the basis of the theoretical assumption that NE-differentiated tumours may be associated with an adverse prognosis and greater chemosensitivity. However, the results of these studies are conflicting: some have found that NE differentiation has a negative impact on survival, but others have failed to demonstrate any correlation with prognosis. Similar discrepancies have also been observed in terms of chemosensitivity. Nevertheless, these data are difficult to interpret because there is no gold standard defining NE differentiation, as is shown by the fact that the proportion of NE-differentiated NSCLCs varies according to the technique and marker used, although chromogranin A and synaptophysin show the best correlation with ultrastructural evidence of NE differentiation. In conclusion, there is no doubt that caution is required when interpreting the results of a number of studies questioning the clinical impact of the NE features of NSCLCs.

[Combination of 5-Fluorouracil and folinic acid--is it still the standard therapy for advanced colorectal carcinoma?]. / La combinazione di 5-FU/FA rappresenta ancora la terapia standard per il carcinoma del colon-retto in stadio avanzato?

After a long period in which the only therapeutic approach for the management of colorectal cancer was the optimization of fluoropyrimidine-based chemotherapy, the last few years have seen the emergence of newly active chemotherapeutic agents endowed with novel mechanisms of action, such as oxaliplatin (OHP), irinotecan (CPT11), raltitrexed and oral 5-fluorouracil (5-FU) pro-drugs which can offer new therapeutic possibilities. The availability of these different classes of cytotoxic agents has introduced the possibility of combination chemotherapy. The most widely studied combinations are 5-FU/folinic acid (FA)/CPT11 and 5-FU/FA/OHP, both of which have been tested in two randomized studies. These trials consistently demonstrated that the addition of CPT11 or OHP to widely accepted infusional/bolus 5-FU/FA regimens is superior to the same 5-FU/FA schedule alone in term of response rate (rate of about > 50%) and time to progression. It's worth nothing that both trials with the combination of 5-FU/FA/CPT11 showed a significant survival benefit. Toxicity profiles were more pronounced with the combination therapies but the quality of life evaluation showed that the combinations had no negative impact on the evolution of the global health status over time. A current ongoing randomized study compares 5-FU/FA/CPT11 with 5-FU/FA/OHP in order to identify the best first-line chemotherapy. Preliminary results in terms of objective response and toxicity are similar for both treatments. Raltitrexed is a thymidilate synthase inhibitor with activity comparable to 5-FU and a convenient administration schedule. In our institution, we performed a phase II single center trial to assess the efficacy of the combination of raltitrexed and CPT11. The principal aim of the study was the overall response rate. We observed a very promising 51% overall response rate. Most relevant side effects were diarrhea in about 20% of patients, asthenia and vomiting. Two recent studies have assessed the efficacy and tolerability of raltitrexed-OHP combination therapy. The results showed that the combination is active (ORR: 46-62%) and tolerable. Promising results have also been obtained in phase I studies with the OHP/CPT11 combination. All these data need to be confirmed in phase II-III clinical trials. In conclusion, combination therapy with CPT11 plus 5-FU/FA produces a 2-3 month survival advantage over 5-FU/FA alone and represents the new reference in the first-line chemotherapy of colorectal cancer. The association of 5-FU/FA and OHP improves response rates and progression-free survival. The increase in toxicity of these combinations is predictable and reversible and does not compromise quality of life. These important data suggest that there is now a limited role for single-agent first-line chemotherapy of metastatic colorectal cancer.